There has been increasing evidence for an important role of natural killer (NK) cells in resistance against cancer and particularly inhibition of the development of metastases. Based on preclinical and clinical indications of significant therapeutic efficacy of lymphokine-activated killer (LAK) cells when administered in combination with high dose interleukin 2 (IL2), and the demonstration that most LAK activity is attributable to IL2-activated NK cells, the therapeutic potential of activated NK cells has been a major area of research at the University of Pittsburgh Cancer Institute (UPCI). The experience to date at the UPCI and other laboratories has shown only limited therapeutic efficacy for this approach. However, in some animal tumor models and in some patients with metastatic cancer, adoptive immunotherapy with IL2-activated NK cells plus IL2 has resulted in partial or even complete tumor regression and prolongation of survival, and such positive results have provided the challenge to improve NK cell based therapy and to make it more frequently and completely effective. This represents the overall theme of the proposed Program Project. In order to succeed, we believe that it will be necessary to understand the mechanisms underlying both the limited successes and the frequent failures, and to then utilize the insights gained to rationally devise improved therapeutic strategies. The overall hypothesis that guides our proposed research is that the potential therapeutic activity of NK cells is dependent on accumulation within metastases of effector cells with sustained high levels of therapeutically-relevant functional activity. Although our ultimate objective is to improve clinical therapy of cancer patients, the need to systematically examine multiple parameters and explore mechanisms dictates extensive preclinical studies to elucidate the main biological principles that are likely to be clinically relevant. Since each animal model has its inherent limitations, we have chosen to explore several in parallel, with the expectation that findings that transcend a particular model system are most likely to be applicable to the design of clinical studies. In addition, to complement studies of adoptive immunotherapy with activated NK cells and IL2, we propose to also examine the therapeutic strategies based on stimulation of accumulation of endogenous NK cells within tumor lesions and reversal of tumor- induced inhibition of the in situ effector cell function.